The cdc5 family of protein kinases has a major role in the regulation of the cell cycle in eukaryotes. In order to determine the role of the cdk5 in brain development, we created cdk5 knock-out (-/-) mice. The life-span of these mice was greatly shortened. The brains of these mice lack cortical laminar structure and cerebellar foliation. Recent studies revealed that the Cdk5 (-/-) thalamic axons project through the cerebral cortex with abnormal trajectories and cortical plate neurons were inverted according to their birth date. The cells of the preplate were separated into subplate and marginal zone by neurons with the morphology of normal pyramidal neurons. Some of the axons of these cells projected correctly to the thalamic anlage. The results suggest that further cortical development is blocked in the Cdk5 (-/-) mice at an intermediate stage soon after the splitting of the preplate. Comparison with Cdk5 (-/-) with reeler and scrambler mice indicates that the cdk5 deficiency causes distinct pathological changes. The results suggest that Cdk5 participates in a separate, perhaps parallel, pathway of brain development.